Updated Pharmacological Effects, Molecular Mechanisms, and Therapeutic Potential of Natural Product Geniposide.

At present, the potential of natural products in new drug development has attracted more and more scientists' attention, and natural products have become an important source for the treatment of various diseases or important lead compounds. Geniposide, as a novel iridoid glycoside compound, is an active natural product isolated from the herb Gardenia jasminoides Ellis (GJ) for the first time; it is also the main active component of GJ. Recent studies have found that geniposide has multiple pharmacological effects and biological activities, including hepatoprotective activity, an anti-osteoporosis effect, an antitumor effect, an anti-diabetic effect, ananti-myocardial dysfunction effect, a neuroprotective effect, and other protective effects. In this study, the latest research progress of the natural product geniposide is systematically described, and the pharmacological effects, pharmacokinetics, and toxicity of geniposide are also summarized and discussed comprehensively. We also emphasize the major pathways modulated by geniposide, offering new insights into the pharmacological effects of geniposide as a promising drug candidate for multiple disorders.

Phytochemistry, synthesis, analytical methods, pharmacological activity, and pharmacokinetics of loganin: A comprehensive review.

Iridoid glycosides (IGs) are found in many medicinal and edible plants, such as Gardenia jasminoides, Cistanche tubulosa, Eucommia ulmoides, Rehmanniae Radix, Lonicera japonica, and Cornus officinalis. Loganin, an IG, is one of the main active ingredient of Cornus officinalis Sieb. et Zucc., which approved as a medicinal and edible plant in China. Loganin has been widely concerned due to its extensive pharmacological effects, including anti-diabetic, antiinflammatory, neuroprotective, and anti-tumor activities, etc. Studies have shown that these underlying mechanisms include anti-oxidation, antiinflammation and anti-apoptosis by regulating a variety of signaling pathways, such as STAT3/NF-κB, JAK/STAT3, TLR4/NF-κB, PI3K/Akt, MCP-1/CCR2, and RAGE/Nox4/p65 NF-κB signaling pathways. In order to better understand the research status of loganin and promote its application in human health, this paper systematically summarized the phytochemistry, analysis methods, synthesis, pharmacological properties and related mechanisms, and pharmacokinetics based on the research in the past decades.

Simultaneous determination of six components of Danzhi Xiaoyao Pill in beagle plasma by HPLC-MS/MS and a study of pharmacokinetic of paeoniflorin and geniposide after single-dose administration.

This study was to develop a reliable and simple high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to detect paeoniflorin, geniposide, saikosaponin b2, liquiritin, paeonol and atractylenolide Ⅲ in beagle plasma and to study pharmacokinetic of paeoniflorin and geniposide after single-dose administration of Danzhi Xiaoyao Pill (DZXY). Chromatographic separation was performed using an Agilent C18 column, and multiple reaction monitoring (MRM) mode was used. A gradient elution procedure was used with solvent A (acetonitrile) and solvent B (0.1 % formic acid-water) as mobile phases. The elution procedure was as follows: 85 % B-30 % B (0-7 min) and 30 % B-30 % B (7.1-8 min). The flow rate was 0.3 mL/min. The column temperature was 40 ℃, and the injection volume was 10 µL. The main analytical parameters of paeoniflorin, geniposide, saikosaponin b2, liquiritin, paeonol and atractylenolide Ⅲ were m/z 525→449, m/z 433→224, m/z 780→617, m/z 417→254, m/z 167→43 and m/z 249→231, respectively. Ethyl acetate was used to extract the analytes in the plasma. Standard calibration curves of six analytes showed satisfactory linearity (r2≥0.99 2) within the determined ranges. The lower limits of quantification were 0.5 ng/mL for paeoniflorin and liquiritin, 2.5 ng/mL for geniposide and saikosaponin b2 and 1.0 ng/mL for atractylenolide Ⅲ and paeonol, respectively. The intra-day and inter-day precision (RSD %) were all below 6.94 %, and the intra-day and inter-day accuracy (RE %) were within ± 6.10 %. The recovery and ME of six analytes were 85.99 %-98.10 % and 95.78%-108.06%, respectively. Additionally, the method we established in this experiment can be successfully used to study the pharmacokinetics of paeoniflorin and geniposide in beagle plasma.

A novel insight into the potential toxicity mechanisms of Zhi-Zi-Hou-Po decoction by dynamic urinary metabolomics based on UHPLC-Q-Exactive Orbitrap-MS.

In recent years, depression occurs frequently. Given the long duration of the disease and the high risk of recurrence, the treatment of depression requires long-term medication. Zhi-Zi-Hou-Po Decoction (ZZHPD) has been used in clinical treatment of depression and related diseases for many years, and the potential toxic damage caused by its long-term use has gradually emerged. Existing research methods that expose toxicity by a one-time administration of large doses cannot provide a reference for clinical safe drug use. In this study, the potential toxicity of ZZHPD in repeated administration was studied by urinary metabolomics with nondestructive sampling. Based on ultra-high performance liquid chromatography-quadruple-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap-MS) and chemometrics, 33 differential biomarkers, such as 3-hydroxybutyric acid, indole sulfuric acid, hippuric acid and citric acid, were screened and dynamically tracked. The changes of some endogenous substances showed obvious time dependence. Further analysis of these time-dependent components in combination with network pharmacology revealed that the potential hepatotoxicity and nephrotoxicity of ZZHPD were related to the disorders of amino acid metabolism, energy metabolism, lipid metabolism, nucleotide metabolism and gut microflora metabolism pathway. This study can better grasp the occurrence and development of drug toxicity, and provide reference for rational and safe drug use and potential toxicity prevention of ZZHPD.

Identification of prototypes from Ligustri Lucidi Fructus in rat plasma based on a data-dependent acquisition and multicomponent pharmacokinetic study.

The identification and quantization of traditional Chinese medicine (TCM) are a challenge for researchers and industry. Using untargeted analytical methods, the in vivo detection and identification of TCM compounds are difficult because of the significant interference of endogenous substances. Fortunately, the ongoing development of new analytical technologies, especially Q-Orbitrap-MS, offers some solutions. Our team developed a holistic MS method, combining untargeted data-dependent MS2 (dd-MS2 ) modes to extensively identify TCM prototypes in vivo. The method was successfully applied to the analysis of Ligustri Lucidi Fructus (LLF). LLF is a widely used TCM with a remarkable nourishing effect on the liver and kidney. In the study, we aimed to identify the prototypes in rat plasma after oral administration of LLF extract. Following separation on an HSS T3 column, LLF extract and rat plasma were performed in untargeted dd-MS2 mode. Forty-seven compounds were characterized in rats plasma as prototypes of LLF extract. Furthermore, seven major prototypes were chosen as pharmacokinetic markers to investigate LLF's pharmacokinetic properties. The results provides comprehensive determination of compounds in LLF both in vitro and in vivo, which is important for quality control, pharmacology studies and clinical use of LLF.

Uncovering pharmacological mechanisms of Zhi-Zi-Hou-Po decoction in chronic unpredictable mild stress induced rats through pharmacokinetics, monoamine neurotransmitter and neurogenesis.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-Zi-Hou-Po decoction (ZZHPD), a classical Chinese prescription, has been reported to improve depressive behaviors in clinic. However, definite pharmacological effects and mechanisms of ZZHPD on monoaminergic system and hippocampal neurogenesis are ambiguous. It need to be further illuminated. AIM OF THE STUDY: Our study is designed to reveal pharmacological mechanisms of ZZHPD on depression through pharmacokinetics, monoamine neurotransmitters and neurogenesis. MATERIALS AND METHODS: Chronic unpredictable mild stress (CUMS) is used to establish rats model of depression. Then, the antidepressant effects of ZZHPD are evaluated by detecting body weight, sucrose preference and forced swimming test. The regulatory functions of ZZHPD on monoaminergic system are assessed by measuring monoamine neurotransmitters, neurotransmitter precursor substances, synthesized rate-limiting enzymes and transporters. Finally, potential molecular mechanism of ZZHPD on hippocampal neurogenesis is evaluated by investigating newborn immature neuron and newborn mature neuron. RESULTS: Our results show that ZZHPD remarkably normalizes CUMS-induced decline in weight gain, decrease of sucrose consumption rate in sucrose preference test and increase of immobility time in forced swimming test. Moreover, ZZHPD significantly reverses CUMS-induced reduction of 5-hydroxytryptamine (5-HT), dopamine (DA), tryptophan (Trp), tyrosine (Tyr), tryptophan hydroxylase2 (TPH2) and tyrosine hydroxylase (TH), whereas decreases level of serotonin transporter (SERT) in CUMS-induced rats. Finally, ZZHPD obviously improves CUMS-induced decrease of newborn immature neuron and newborn mature neuron in dentate gyrus of hippocampus. CONCLUSION: This study demonstrates that ZZHPD can alleviate CUMS-induced depression-like behaviors. It is probably attributed to the fact that ZZHPD could enhance monoaminergic system and hippocampal neurogenesis. Our findings provide the new perspectives on molecular targets of ZZHPD, and it will facilitate its clinical application.

Antioxidative Property and Molecular Mechanisms Underlying Geniposide-Mediated Therapeutic Effects in Diabetes Mellitus and Cardiovascular Disease.

Geniposide, an iridoid glucoside, is a major component in the fruit of Gardenia jasminoides Ellis (Gardenia fruits). Geniposide has been experimentally proved to possess multiple pharmacological actions involving antioxidative stress, anti-inflammatory, antiapoptosis, antiangiogenesis, antiendoplasmic reticulum stress (ERS), etc. In vitro and in vivo studies have further identified the value of geniposide in a spectrum of preclinical models of diabetes mellitus (DM) and cardiovascular disorders. The antioxidative property of geniposide should be attributed to the result of either the inhibition of numerous pathological processes or the activation of various proteins associated with cell survival or a combination of both. In this review, we will summarize the available knowledge on the antioxidative property and protective effects of geniposide in DM and cardiovascular disease in the literature and discuss antioxidant mechanisms as well as its potential applications in clinic.

LC-electrolyte switch in a contiguous time segments to analyze multi-components: Simultaneous determination of phenolic acids and iridoids in rat plasma after inhalation administration of Reduning aerosol.

The optimization of electrolytes, kinds and concentrations, in mobile phase for multiple constituents analyzing using high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS) was usually compromised to ensure good LC separation of partial components. However, the compromised electrolytes could lead to ionization suppression of some of the analytes. To solve the compromise of electrolytes within various components, taking phenolic acids and iridoids as a case, we used electrolyte switch in contiguous running time segments of UPLC-ESI-MS/MS to ensure chromatographic separation of chlorogenic acid, neochlorogenic acid and cryptochlorogenic acid and improve the response of geniposide. Then the method was applied for pharmacokinetic study of the four components in rat after inhaling Reduning aerosol for the first time. The complete separation of the three chlorogenic acid isomers was achieved and the LLOQs of neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, and geniposide were 1, 1, 3, and 0.2 ng/mL, respectively. In conclusion, we developed a sensitive and time-saving LC-MS/MS method for the quantitative analysis of chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid, and geniposide in rat plasma, and this method appears to be useful for pharmacokinetic studies of Reduning aerosol. The method provided a sight to alleviate compromise of electrolytes in mobile phase for HPLC-ESI-MS in analyzing multi-components.

Comparative pharmacokinetic study of four major bioactive components after oral administration of Zhi-Zi-Hou-Po decoction in normal and corticosterone-induced depressive rats.

A highly selective and efficient LC-MS/MS method was developed to determine the plasma concentration of magnolol, hesperidin, neohesperidin and geniposide following oral administration of Zhi-Zi-Hou-Po decoction in normal and depressed rats. Plasma samples were pretreated by protein precipitation with methanol. Chromatographic separation was performed on an XTerra® MS C18 column using a gradient elution with a mobile phase composed of acetonitrile-0.1% aqueous formic acid. The proposed method was validated to be specific, accurate and precise for the analytes determination in plasma samples. The calibration curves displayed good linearity over definite concentration ranges for the analytes. The intra- and inter-day precision of the proposed method at three different levels were all within <11.13% and the relative errors ranged from -8.46 to 8.93%. The recovery of the four compounds ranged from 82.72 to 89.08% and no apparent matrix effect was observed during sample analysis. After full validation, the established method was successfully applied for comparing the pharmacokinetics of four components between normal and depressed rats. The results showed that the AUC and Cmax of four analytes in depressed rats were significantly different from those in normal rats and might provide helpful information to guide the clinical use of Zhi-Zi-Hou-Po to treat depression.

[Pharmacokinetics of Achyranthes bidentata on adjuvant arthritis rats by microdialysis and UHPLC-MS/MS].

To investigate the " drug-guide" effect of Achyranthes bidentata saponins( ABS) and geniposide( GE) in the treatment on adjuvant arthritis( AA) rats. A UHPLC-MS/MS method for the quantitative determination of GE,zingibroside R1,ginsenoside Ro and chikusetsu saponin Ⅳa in rat blood and joint dialysate was established. After single or combined administration with ABS and GE was given to AA rat model,a microdialysis sampling method for rat joint cavity and jugular vein blood vessels was established to collect microdialysis samples. Waters Acquity HSS C_(18) column was used to separate the above four components,with mobile phase as acetonitrile-0. 1% formic acid water as mobile phase for gradient elution. ESI source was adopted for mass spectra in a negative ion scanning mode. Multiple reaction monitoring( MRM) mode was applied to detect the above four components. The methodological results showed that GE,zingibroside R1,ginsenoside Ro and chikusetsu saponin Ⅳa demonstrated a good linear relationship within the concentration ranges of 2-4 000,16-4 096,14-3 584,23-5 888 µg·L-1 respectively. The precision,accuracy,stability and matrix effect of these four ingredients reached the requirements of quantitative analysis of biological samples. The pharmacokinetic results demonstrated that the combined administration of ABS and GE( 60 mg·kg~(-1)+60 mg·kg~(-1)) can increase the degree of GE in joint cavity distribution,and the AUCjoint/AUCplasmwere twice of that of single administration of GE( 60 mg·kg~(-1)),which indicated that ABS might played a vital role in GE's distribution to joint cavity. Moreover,there was no significant difference between the distribution trend of total three ABS and GE in rats. The pharmacodynamics results showed that the combined administration of ABS and GE has stronger effects on paw swelling,arthritis index and synovial pathomorphology of AA rats than single administration of GE,which suggested that ABS might improve GE's anti-inflammatory effect in AA rats. Based on the above results,ABS has a targeting effect in increasing GE's concentration in joint cavity,with a synergy in efficacy.

Evaluation of the Hepatotoxicity of the Zhi-Zi-Hou-Po Decoction by Combining UPLC-Q-Exactive-MS-Based Metabolomics and HPLC-MS/MS-Based Geniposide Tissue Distribution.

With traditional Chinese medicine (TCM) becoming widespread globally, its safety has increasingly become a concern, especially its hepatoxicity. For example, Gardenia jasminoides Ellis is a key ingredient in the Zhi-Zi-Hou-Po decoction (ZZHPD), which is a commonly-used clinically combined prescription of TCM that may induce hepatoxicity. However, the underlying toxicity mechanism of ZZHPD is not fully understood. In this study, a plasma metabolomics strategy was used to investigate the mechanism of ZZHPD-induced hepatotoxicity through profiling entire endogenous metabolites. Twenty-four Sprague-Dawley rats were randomly assigned into four groups, which were orally administered with 0.9% saline, as well as 2.7 g/kg/day, 8.1 g/kg/day, or 27 g/kg/day of ZZHPD for 30 consecutive days, respectively. Biochemical assay and metabolomics assay were used to detect serum and plasma samples, whilst histopathological assay was used for detecting liver tissues, and the geniposide distribution in tissues was simultaneously measured. The results showed that the concentration of 20 metabolites linked to amino acid, lipid, and bile acid metabolism had significant changes in the ZZHPD-treated rats. Moreover, toxic effects were aggravated with serum biochemical and histopathological examines in liver tissues as the dosage increased, which may be associated with the accumulation of geniposide in the liver as the dosage increased. Notably, our findings also demonstrated that the combined metabolomics strategy with tissue distribution had significant potential for elucidating the mechanistic complexity of the toxicity of TCM.

Deciphering the absorption profile and interaction of multi-components of Zhi-Zi-Da-Huang decoction based on in vitro-in silico-in vivo integrated strategy.

Zhi-Zi-Da-Huang decoction (ZZDHD) has been acknowledged with striking therapeutic effects for hepatobiliary disorders in the history of China. As decoctions are usually administrated orally, intestinal absorption, the prerequisite task of exerting therapeutic effects, is of utmost significance for screening potential active compounds and understanding the mechanism of drug action. In this work, an in vitro-in silico-in vivo strategy based on HPLC-DAD-ESI-TOF/MS was adopted for precisely profiling the intestinal absorption of ZZDHD, which integrated information obtained from rat everted gut sac model, octanol-water partition model, in silico prediction and in vivo experimental data. Besides, 34 main absorbed ingredients were selected as chemical markers to investigate the compatible interaction of the decoction on absorption level using rat everted gut sac experiment. In total, 106 compounds of ZZDHD were speculated as potential absorptive. Among them, 90 constituents predicted absorbable in at least two experimental models were finally recognized as intestinal absorbable ingredients. In addition, the absorption level of iridoids, terpenoids and flavonoid glycosides were found improved and the absorption of catechins and anthraquinones were inhibited after prescription compatibility. Taken together, this study presents a reliable strategy for evaluating intestinal absorption of herbal medicines and offers a reference for the rationality of herbal compatibility and the modernization of traditional Chinese medicine (TCM).

Evaluation of the Absorption Behavior of Main Component Compounds of Salt-Fried Herb Ingredients in Qing'e Pills by Using Caco-2 Cell Model.

Qing'e Pills is a Chinese traditional herbal product, which is often used to strengthen muscles and bones in TCM (traditional Chinese Medicine) practice. Its two main component herbs, namely, Cortex Eucommiae and Fructus Psoraleae are both required to be salt-fried according to TCM theory. We have evaluated the effects of salt-frying treated herbs on Caco-2 cell uptake behavior for those active ingredients of Qing'e Pills. By investigating of various variables, including MTT, temperature, inhibitors, pH, salt concentration and herb processing methods, we tried to clarify whether the salt-processing on herbs was necessary or not. Results showed that, compared to other processing methods, the salt-frying process significantly (p < 0.01) enhanced the absorption of effective components of Qing'e Pills. The way that psoralen, isopsoralen, psoralenoside and geniposide acid entered Caco-2 cells at low concentrations was via passive diffusion. These components were not substrates of P-glycoprotein. It demonstrated that the salt-frying process not only enhanced the concentration of active components in herb extract, but also changed their absorption behaviors. Nevertheless, the mechanism of absorption behavior changing needs to be further investigated.

Preclinical Pharmacokinetics of Scoparone, Geniposide and Rhein in an Herbal Medicine Using a Validated LC-MS/MS Method.

The herbal formula Yin-Chen-Hao-Tang has been reported to have anti-fibrosis properties. The aim of this study was to reveal the pharmacokinetic characteristics of bioactive compounds in this herbal formula. A new high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of scoparone, geniposide and rhein in rat plasma. A pharmaceutical herbal powder was administered to rats at doses of 1 g/kg and 3 g/kg orally. The method showed excellent linearity (r² > 0.999) and validation was successfully conducted for the pharmacokinetic study. The results show that the Cmax values and areas under the curve of scoparone, geniposide and rhein were higher and not proportional to the dose in rat plasma, while the Tmax and half-life values were consistent in the group that received 1 g/kg. The clearance of the higher dose (3 g/kg) did not decrease proportionally to that of the low dose. The results showed the nonlinear pharmacokinetic properties of scoparone, geniposide and rhein in Yin-Chen-Hao-Tang that suggested possible accumulation of bioactive compounds through oral administration. This pharmacokinetic study reveals that an increased dose of this herbal formula would largely increase the maximum concentration and bioavailability of scoparone, geniposide and rhein.

Pharmacokinetics and tissue distribution of monotropein and deacetyl asperulosidic acid after oral administration of extracts from Morinda officinalis root in rats.

BACKGROUND: Iridoid glycosides (IGs), including monotropein (MON) and deacetyl asperulosidic acid (DA) as the main ingredients, are the major chemical components in Morinda officinalis How. (MO) root, possessing various pharmacological properties including anti-osteoporosis, anti-inflammation and anti-rheumatism activities.The aim of the present study was to further elucidate the pharmacological actions of MO by investigating the pharmacokinetics and tissue distribution of IGs in MO. METHODS: An ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) method was developed and validated for simultaneous determination of MON and DA levels in plasma and various tissues of Wistar rats. MON, DA and acetaminophen (ACE) as the internal standard (IS) were extracted from rat plasma and tissue samples by direct deproteinization with methanol. The rats were administered orally at 1650 mg/kg MO and 25, 50 and 100 mg/kg MO iridoid glycosides (MOIGs) or intravenously at MOIG 25 mg/kg for pharmacokinetic study of MON and DA. In addition, 100 mg/kg MOIG was administered orally for tissue distribution study of MON and DA. Non-compartmental pharmacokinetic profiles were constructed. Tissue distributions were calculated according to the validated methods. RESULTS: Significant differences in the pharmacokinetic parameters were observed in male and female rats. The AUC0-t, Cmax and bioavailability of MON and DA in female rats were higher than those in male rats. MON and DA mainly distributed in the intestine and stomach after oral administration, and noteworthily high concentrations of MON and DA were detected in the rat hypothalamus. CONCLUSION: The results of the present study may shed new lights on the biological behavior of MOIGs in vivo, help explain their pharmacological actions, and provide experimental clues for rational clinical use of these IGs extracted from the MO root.

Metabolite profile analysis and pharmacokinetic study of emodin, baicalin and geniposide in rats.

1. Emodin, baicalin and geniposide are the major bioactive components in Da-Huang, Huang-Qin and Zhi-Zi which are herbal medicines widely used in Asian nations. 2. The metabolism of the three compounds was found to undergo hydroxylation, decarboxylation, dehydration, methylation, hydrolysis, hydrogenation, dihydrogenation, sulfation, glucosidation and/or glucuronidation. A total of 63 metabolites were detected in urine, plasma and bile of rats given a mixture of the three compounds. 3. Pharmacokinetic properties of the three compounds were determined in rats given the extracts of Da-Huang, Huang-Qin and Zhi-Zi. The pharmacokinetic parameters for emodin, baicalin and geniposide were found to be 0.13 ± 0.11, 0.25 ± 0.12 and 0.40 ± 0.09 h (Tmax); 21 ± 9, 1515 ± 254 and 482 ± 50 ng/mL (Cmax); 8.6 ± 5.5, 18.3 ± 2.8 and 22.1 ± 17.2 h (t1/2); 29 ± 20, 16886 ± 3734 and 2936 ± 551 ng/mLch (AUC(0-t)); and 37 ± 20, 22624 ± 6295 and 3582 ± 820 ng/mLch (AUC(0-∞)). 4. The metabolism and pharmacokinetic studies facilitate appropriate employment of Da-Huang, Huang-Qin and Zhi-Zi in clinic.

[Effect of wintergreen oil on in vitro transdermal permeation of osthole and geniposide].

The aim of this study was to investigate the transdermal penetration enhancement effect of wintergreen oil and its action mechanisms. The in vitro transdermal tests were carried out to study the transdermal penetration enhancement effect of wintergreen oil by using osthole and geniposide as the lipophilic and hydriphilic model drugs. Fourier-transform infrared spectroscopy was used to investigate the effect of wintergreen oil on the molecular structure of rat stratum corneum, and the scanning electron microscope was employed to observe the change of rat skin surface after treatment by the oil. The wintergreen oil at proper concentrations could effectively promote the transdermal permeation of osthole and geniposide, and exhibited better penetration-enhancing activity for the lipophilic osthole, close to the commonly used classical penetration enhancer azone. The infrared spectroscopy study and scanning electron microscope showed that wintergreen oil mainly acted on the stratum corneum lipids, reduced dense stratum corneum, and reduced the skin barrier function. Thus, the wintergreen oil could effectively facilitate the transdermal absorption of the lipophilic and hydrophilic drugs, resulting from the lowed skin barrier function.

A Review on the Phytochemistry, Pharmacology, Pharmacokinetics and Toxicology of Geniposide, a Natural Product.

Iridoid glycosides are natural products occurring widely in many herbal plants. Geniposide (C17H24O10) is a well-known one, present in nearly 40 species belonging to various families, especially the Rubiaceae. Along with this herbal component, dozens of its natural derivatives have also been isolated and characterized by researchers. Furthermore, a large body of pharmacological evidence has proved the various biological activities of geniposide, such as anti-inflammatory, anti-oxidative, anti-diabetic, neuroprotective, hepatoprotective, cholagogic effects and so on. However, there have been some research articles on its toxicity in recent years. Therefore, this review paper aims to provide the researchers with a comprehensive profile of geniposide on its phytochemistry, pharmacology, pharmacokinetics and toxicology in order to highlight some present issues and future perspectives as well as to help us develop and utilize this iridoid glycoside more efficiently and safely.

Integrating UHPLC-MS/MS quantification and DAS analysis to investigate the effects of wine-processing on the tissue distributions of bioactive constituents of herbs in rats: Exemplarily shown for Dipsacus asper.

Wine-processing, which is sauteing with rice wine, will change the inclination and direction of herbs' actions. After being wine-processed, the effects of nourishing liver and kidney of Dipsacus asper will be strengthened. However, the underlying mechanism remains elusive. The following study is to establish and validate an UHPLC-MS/MS approach to determine six bioactive constituents in tissue samples, including loganin, loganic acid, chlorogenic acid, 3,5-dicaffeoylquinic acid, 4-caffeoylquinic acid and asperosaponin VI and apply the approach to a comparative tissue distribution study of raw and wine-processed Dipsacus asper in rats. A Shimadzu UHPLC system coupled with triple quadrupole mass spectrometer was employed for analysis of the six analytes using multiple reaction monitoring (MRM) mode. A one-step protein precipitation by methanol was employed to extract the six analytes from tissues. Chloramphenicol and glycyrrhetinic acid were selected as internal standards. The proposed approach was fully validated in terms of linearity, sensitivity, precision, repeatability as well as recovery. Our results revealed that all of the calibration curves displayed good linear regression (r2>0.9991). Intra- and inter-assay variability for all analytes ranged from -4.62 to 4.93% and from -4.98 to 4.92%, respectively. The recovery rates for each analytes were determined to be 88.3-100.1%. All the samples showed satisfactory precision and accuracy after various stability tests, including storage at 25°C for 4h, -80°C for 30days, three-freeze-thaw cycles, and 4°C for 24h. Tissue pharmacokinetic parameters including AUC0-t, t1/2, Tmax and Cmax were calculated. Collectively, the parameters of Cmax and AUC0-t of the six analytes in wine-processed group were remarkably elevated (p<0.05) in the rat liver and kidney as compared with those of the raw group. But in the rat heart and spleen, the Cmax and AUC0-t of asperosaponin VI was decreased as compared with those of the raw group. The accumulation of bioactive constituents in liver and kidney tissues after wine-processing will contribute to the enhancement of liver and kidney nourishing effects.

Pharmacokinetics and comparative metabolic profiling of iridoid enriched fraction of Picrorhiza kurroa - An Ayurvedic Herb.

ETHNO-PHARMACOLOGICAL RELEVANCE: Picrosides I, II and apocynin are the main active principles present in the roots and rhizomes of Picrorhiza kurroa Royle ex. Benth (Kutki). Ethno-medicinally, the plant is used for the treatment of liver, upper respiratory tract disorders and dyspepsia, since long in Ayurveda. AIM OF THE STUDY: This study attempts to determine the pharmacokinetic profile of picrosides I, II and apocynin in rats after oral administration of iridoid enriched fraction (IRF) and to recognize the pattern of its metabolites as such in IRF and in plasma. MATERIALS AND METHODS: A simple, precise, specific and sensitive RP-HPLC method was developed for simultaneous quantification of picrosides I, II and apocynin in rat plasma and in plant extract. Acetonitrile (ACN) and water was used as a solvent system with a gradient elution for pharmacokinetic studies using HPLC-PDA (Flow rate: 1.0mL/min) and metabolic profiling through UPLC-MS (Flow rate: 0.5mL/min) in selected reaction monitoring. A comparative study was performed in order to recognize the pattern and fate of metabolites in rat plasma up to 24h after single oral administration of IRF. RESULTS: Developed method produced more than 85% recovery of the targeted metabolites in rat plasma. The content of picrosides I, II and apocynin in IRF were found 5.7%, 18.3% and 27.3% w/w, respectively. The mean plasma concentration versus time profiles of picroside I, II and apocynin resulted in peak plasma concentration (Cmax) 244.9, 104.6 and 504.2ng/mL with half-life (t1/2) 14, 8 and 6h, respectively. Other pharmacokinetic parameters such as time to reach Cmax (tmax), area under curve (AUC), absorption (ka) and elimination (ke) constant, volume of distribution (Vd) were also determined. Pattern recognition analysis showed fate of 18 metabolites in rat plasma up to 24h out of 26 present in IRF. CONCLUSION: The information gained from this study postulates the basic pharmacokinetic profiling of picroside I, II and apocynin as well as fate of other metabolites after oral administration of IRF, demonstrating scientific basis of its traditional use in Ayurveda.